Background: Survival rates from breast cancer have improved; however, many breast cancer survivors experience treatment-induced adverse effects including late-onset cardiovascular disease due to radiation therapy. Radiation-induced cardiovascular disease (RICVD), which can appear 5 ? 10 or more years after radiation, is a substantial cause of increased morbidity and mortality among breast cancer survivors. Currently, it is not known how to best identify individuals who will develop RICVD, as RICVD often occurs years after treatment and is often neglected in research due to the expense of following participants long-term. As a result, the primary body of literature in cardio-oncology examines short-term cardiac outcomes, mainly related to chemotherapy. Based on these studies, biomarkers of cardiac damage and inflammation have been identified as acute contributors of cardiotoxicity. While RICVD likely shares some pathways of chemotherapy-induced CVD, this has not been definitively tested in research studies. Pathways, such as oxidative stress and fibrosis, are thought to play a large role in the development of RICVD. Purpose: The purpose of this study is to examine post-treatment serum biomarkers of oxidative stress (8-OH-dG, MPO), fibrosis (TGF-B), cardiac damage (TnI-I, cystatin-C), and inflammation (IL-6, GDF-15, CRP) in the development of long-term RICVD in breast cancer survivors treated with radiation and to stratify by right- vs. left-sided radiation. Specifically, we aim to 1) to examine the risk of RICVD and CVD death in breast cancer survivors treated with radiation (vs. controls) associated with biomarkers (post-treatment), 2) to examine the risk of RICVD and CVD death (vs. controls) comparing breast cancer survivors treated with right-sided radiation vs. left-sided radiation, and 3) to examine the association of post-treatment biomarkers in the risk of RICVD and CVD death (vs. controls) among breast cancer survivors, stratified by right- vs. left-sided radiation. Methods: We propose a nested, case-control design within the Women's Health Initiative Life and Longevity After Cancer (WHI LILAC), a national, prospective, cohort study. Inclusion criteria are: 1) serum sample available at WHI baseline and year 3 and 2) a breast cancer diagnosis and radiation treatment between the two serum collection time points. All biomarkers will be assessed at both timepoints using ELISA. Women with an adjudicated heart failure, myocardial infarction, coronary coronary heart disease, or other cardiovascular death outcome occurring post-breast cancer will constitute the case group (n = 56) while women without a RICVD outcome will constitute the control group (n = 128). Logistic regression will be used. Summary: This study leverages the WHI dataset, which is an excellent cohort to address the identified research gaps, given the availability of biospecimens previously collected from participants with nearly 20 years of outcome follow-up. This study is significant as it will investigate biomarkers targeting multiple, relevant pathways potentially associated with RICVD, which could be used in future studies to improve the identification and prediction of RICVD in cancer survivors.